![]() McKinney et al., 1977.) Campylobacter infections also occur in XLA. Systemic enterocytopathogenic human orphan virus (ECHO), coxsackievirus, and vaccine-related polio infections, harbored in the intestinal tract, have caused severe morbidity and high mortality rates among XLA patients (R.E. coli infection ( Lederman and Winkelstein, 1985). Nine patients of the group were found to have infections with Giardia lamblia there was one case each of salmonella infection and enteropathogenic E. On clinical presentation, 31 of 98 patients in the largest reported series of XLA patients had acute gastrointestinal infections and 3 had perirectal abscesses, but chronic gastrointestinal tract infections were found in only 10 of the 98 patients (10.2% for XLA, as opposed to 32% to 80% in CVID). Gastrointestinal disease Infectious and inflammatory diseaseĪlthough male infants may first present with gastrointestinal disease, chronic gastrointestinal disease appears less commonly in XLA than in CVID. Plasma cells are lacking and there is no immunoglobulin secretion in mucosal fluids. In classic cases of XLA, there are no lymphoid germinal centers, and nodular lymphoid hyperplasia does not develop. Males with XLA usually become ill in the first year of life, commonly experiencing respiratory or gastrointestinal tract infections ( Lederman and Winklestein, 1985). The hallmark of the illness is very low to absent serum immunoglobulins and absent or nearly absent circulating B cells. X-linked agammaglobulinemia (XLA), a more uncommon humoral immune defect than CVID, is due to an abnormality of an X chromosome–encoded B-cell cytoplasmic tyrosine kinase necessary for B-cell maturation ( Conley et al., 1994). However, additional factors, including other genes, past infections and therapy, may also influence the phenotype of patients with XLA.Ĭharlotte Cunningham-Rundles, in Mucosal Immunology (Third Edition), 2005 X-LINKED AGAMMAGLOBULINEMIA Inheritance and immunologic defects Amino acid substitutions in the SH2 domain or noncritical regions of the catalytic domain are sometimes seen in patients with milder disease. Thus, these mutations are functionally equivalent.Īttempts to correlate the severity of the clinical manifestations of XLA with specific mutations in Btk suggest that the site or type of mutation may influence the phenotype. Studies done on EBV-transformed cell lines or myeloid cells from patients with XLA indicate that this last group of mutations (stop codons, frameshifts and splice defects) usually result in poor accumulation of the Btk mRNA in the cytoplasm. These mutations are spread almost evenly throughout the Btk gene. The remaining mutations are almost equally divided between single base pair substitutions that cause premature stop codons, small insertions or deletions that result in frameshift mutations and splice defects. About one-third of the mutations result in amino acid substitutions, the majority of which are in the kinase domain however, amino acid substitutions in the PH domain and the SH2 domain have also been seen. Although deletions that are detectable by Southern blot analysis do occur, they constitute less than 10% of the mutations in this gene. Over 100 different mutations in Btk have been identified. ![]() Human Btk has over 95% homology to murine Btk and 58% homology to a drosophila kinase, Dsrc28C. ![]() The gene for Btk consists of 19 exons spread over 37 kb at Xq22. Second, the mutations in Btk that cause XLA are independently derived and highly variable. First, approximately half of the patients with the clinical and laboratory characteristics of XLA have no family history of the disorder because they are the first manifestation in their family of a new mutation. As is true with all X-linked disorders that are lethal without medical intervention, the disorder is maintained in the population by the occurrence of new mutations. Mary Ellen Conley, in Encyclopedia of Immunology (Second Edition), 1998 Geneticsīrutons agammaglobulinemia occurs in all racial groups, with a prevalence of between 2 and 8 per 1 000 000. ![]()
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